Akt kinase (hereafter, referred to as “Akt”) is serine/threonine kinase, which is also referred to as “PKB,” and it is a molecule playing a key role in survival, growth, metabolism, and other functions of a cell (Non Patent Literature 1).
In various types of cancers, abnormal activation of Akt or mutation of the Akt gene has been observed, and involvement of Akt in onset, maintenance, and development of cancer phenotype has been strongly implied (Non Patent Literatures 2 and 3).
To date, several Akt-targeting inhibitors have been developed and their antitumor effects have been reported. Such inhibitors, however, do not exert sufficient antitumor effects in the form of single agents on non-clinical models, and strong cytotoxic effects at low concentration or strong antitumor effects in vivo have not yet been achieved (Non Patent Literatures 4 and 5). In addition, no clinical effects have been confirmed concerning such inhibitors.
In the reports that have been made in the past, in addition, cancer types on which the Akt inhibitor exerts certain effects are limited to cells or models of, for example, breast cancer, prostate cancer, and glioma (Non Patent Literatures 4 and 6), and examples exerting strong effects on other cancer species, such as colon cancer, are not known.
Among serine/threonine kinases that phosphorylate the 40S ribosomal protein S6, a kinase with a molecular weight of 90 kDa is referred to as Rsk kinase or p90 Rsk kinase (hereafter, referred to as “Rsk”). Rsk has been reported that it is located downstream of the Ras-Raf-MAPK signaling cascade, it is an important signal transducing molecule having functions of regulating growth, survival, metabolism, and motility of a cell, and it has various functions necessary for cancer cell proliferation (Non Patent Literature 7).
To date, several compounds exerting inhibitory activity against Rsk have been reported (Non Patent Literatures 7, 8, and 9), although the antitumor effects are limited. While it has been reported in non-clinical studies that an Rsk inhibitor has exerted certain effects on lung cancer, breast cancer, thyroid cancer, prostate cancer, and other cancer species in the past, there is no Rsk inhibitor that has been developed in clinical trials.
S6K kinase (hereafter, referred to as “S6K”) is serine/threonine kinase that is indispensable for regulation of phosphorylation of the 40S ribosomal protein S6, as well as Rsk. It is considered that S6K is activated through the PI3K/mTOR signaling pathway upon stimulation of a growth factor, such as an insulin-like growth factor, and S6K regulates cancer through phosphorylation of various functional molecules necessary for various cancer properties (e.g., growth, survival, invasion, and metastasis) (Non Patent Literature 10). Also, ubiquitous high-level expression of S6K in tumors has been reported, and S6K inhibition has been expected to exert antitumor effects.
In recent years, a compound having S6K-selective inhibitory activity was reported. In clinical studies, however, a response has not been achieved at MTD (Non Patent Literature 11).
As piperazine derivatives having inhibitory activities against Akt, Rsk, and S6K, the compounds described in Patent Literatures 1 and 2 have been reported, but antitumor effects thereof are insufficient.
In the field of cancer treatment, accordingly, development of a serine/threonine kinase inhibitor that exhibits strong antitumor effect with a single agent and is effective against various cancers has still been awaited.